EP4076457A1 - Composés hétérocycliques à substitution amido et procédés d'utilisation desdits composés pour traiter les herpèsvirus - Google Patents

Composés hétérocycliques à substitution amido et procédés d'utilisation desdits composés pour traiter les herpèsvirus

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Publication number
EP4076457A1
EP4076457A1 EP20902205.2A EP20902205A EP4076457A1 EP 4076457 A1 EP4076457 A1 EP 4076457A1 EP 20902205 A EP20902205 A EP 20902205A EP 4076457 A1 EP4076457 A1 EP 4076457A1
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EP
European Patent Office
Prior art keywords
compound
alkyl
group
mmol
compounds
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
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EP20902205.2A
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German (de)
English (en)
Other versions
EP4076457A4 (fr
Inventor
Kira A. ARMACOST
Andrew John Cooke
Robert Patrick HAYES
Marc A. Labroli
Michael Aaron Plotkin
Izzat Tiedje RAHEEM
Jeffrey W. Schubert
David M. Tellers
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Merck Sharp and Dohme LLC
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Merck Sharp and Dohme LLC
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Publication of EP4076457A1 publication Critical patent/EP4076457A1/fr
Publication of EP4076457A4 publication Critical patent/EP4076457A4/fr
Pending legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to novel Amido-Substituted Heterocyclic Compounds, compositions comprising at least one Amido-Substituted Heterocyclic Compound, and methods of using the Amido-Substituted Heterocyclic Compounds for treating or preventing herpesvirus infection in a patient.
  • Herpesviridae Human herpes viruses
  • Infection with herpes viruses can occur early in life and by adulthood over 95% of the population is infected by at least one herpes virus.
  • These viruses establish a persistent life-long infection through viral latency in neuronal, lymphoid, or myeloid cells. Recurrent episodes of herpes virus disease can be triggered by numerous stimuli, including concurrent viral infections, stress, fatigue, allergies, pregnancy, sunlight or fever.
  • Herpes virus infection in immune competent individuals generally causes mild self-limiting disease, such as: oral (HSV-1) and genital (HSV-2) ulcers, chicken pox (VZV), flu-like syndrome (CMV) and mononucleosis (EBV).
  • HSV-1 oral
  • HSV-2 genital
  • VZV chicken pox
  • CMV flu-like syndrome
  • EBV mononucleosis
  • primary infection with, or reactivation of an existing herpes virus infection is a major cause of disease and death.
  • Key at-risk immunocompromised populations include patients undergoing solid organ or stem cell transplants, individuals with HIV/AIDS, and ICU patients.
  • Herpesviridae comprise a diverse family of double-stranded DNA viruses that are classified into three subfamilies (i.e., a, b, and g) based upon biological characteristics such as cell tropism, diseases caused, viral life-cycle, and site of viral persistence and latency.
  • the family consists of eight members: Herpes Simplex Virus type 1 and 2 (HSV-1, HSV-2),
  • VZV Varicella Zoster Virus
  • EBV Epstein-Barr virus
  • CMV Cytomegalovirus
  • HHV6-8 human herpes viruses 6-8
  • a-herpes viruses include herpes simplex virus types 1 and 2 (HSV1 and HSV2) and varicella-zoster virus (VZV).
  • HSV1 causes orofacial lesions, commonly known as fever blisters or cold sores. Approximately 30% of the United States population suffers from recurrent episodes of HSV1.
  • HSV2 which is less common than HSV1, causes genital lesions.
  • Primary infection with VZV causes varicella, commonly known as chicken pox. Reactivation of latent VZV manifests as herpes zoster or shingles.
  • Cytomegalovirus is a prototypical b herpes virus. Seroprevalance to CMV in the adult population is -60%, but certain endemic areas of the world have rates closer to 100%. CMV represents the leading viral cause of morbidity and mortality in at-risk immunocompromised patients. EBV, a g herpes virus, causes infectious mononucleosis and is responsible for lymphoid cancers such as Burkitt’s and Hodgkin’s lymphoma.
  • the present invention provides Compounds of Formula or a pharmaceutically acceptable salt thereof, wherein:
  • X is: (a)
  • Z is selected from CH, C(CFb), CF, and N; Z’ is CFh or NH;
  • A is selected from CFh, C(O), and O;
  • B is CFh or N(R 8 );
  • D is CFh or N(R 8 ), provided that B and D cannot both be N(R 8 );
  • R 1 is selected from H, C1-C6 alkyl, -OR 7 ; 5- to 7-membered monocyclic heterocycloalkyl or 9- or 10-membered bicyclic heterocycloalkyl, wherein said 5- to 7- membered monocyclic heterocycloalkyl group, and said 9- or 10-membered bicyclic heterocycloalkyl group can be optionally substituted with up to three R A groups, which can be the same or different;
  • R 2 is 5- to 7-membered monocyclic heterocycloalkyl, which can be optionally substituted with up to three R A groups, which can be the same or different, and wherein said 5- to 7-membered monocyclic heterocycloalkyl group can optionally have a ring carbon atom functionalized as a carbonyl group;
  • R 3 is selected fromH, C1-C6 alkyl, -0-(Ci-C6 alkyl), C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 haloalkyl, -CN, -C(0)0-(Ci-C6 alkyl), and C3-C7 cycloalkyl;
  • R 4 is selected fromH, C1-C6 alkyl, -0-(Ci-C6 alkyl), C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 haloalkyl, -CN, -C(0)0-(Ci-C6 alkyl), and C3-C7 cycloalkyl;
  • R 5 represents up to 3 optional phenyl ring substituents, which can be the same or different, and are each independently selected from halo, -CN, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, -(C1-C6 alkylene)-0-benzyl, -(C1-C6 alkylene)-0-(Ci-C6 alkyl), and -(C1-C6 alkylene)-N(R 7 )2;
  • R 6 is selected from H and halo; each occurrence of R 7 is independently selected from H, C1-C6 alkyl, and C3-C7 cycloalkyl;
  • R 8 is H or C1-C6 alkyl; each occurrence of R A is independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxyalkyl, 5- to 7-membered monocyclic heterocycloalkyl, -C(0)-(Ci-C6 alkyl), and halo; each occurrence of n is independently 0 or 1.
  • the Compounds of Formula (I) (also referred to herein as the “Amido-Substituted Heterocyclic Compounds”), and pharmaceutically acceptable salts thereof can be useful, for example, for inhibiting herpesvirus viral replication or activity, and for treating or preventing herpesvirus infection in a patient. Without being bound by any specific theory, it is believed that the Amido-Substituted Heterocyclic Compounds inhibit herpesvirus viral replication by inhibiting herpesvirus polymerase.
  • the present invention provides methods for treating or preventing herpesvirus infection in a patient, comprising administering to the patient an effective amount of at least one Amido-Substituted Heterocyclic Compound.
  • the present invention relates to novel Amido-Substituted Heterocyclic Compounds, compositions comprising at least one Amido-Substituted Heterocyclic Compound, and methods of using the Amido-Substituted Heterocyclic Compounds for treating or preventing herpesvirus infection in a patient.
  • a “patient” is a human or non-human mammal. In one embodiment, a patient is a human.
  • an effective amount refers to an amount of Amido-Substituted Heterocyclic Compound and/or an additional therapeutic agent, or a composition thereof that is effective in producing the desired therapeutic, ameliorative, inhibitory or preventative effect when administered to a patient suffering from a viral infection or virus-related disorder.
  • an effective amount can refer to each individual agent or to the combination as a whole, wherein the amounts of all agents administered are together effective, but wherein the component agent of the combination may not be present individually in an effective amount.
  • preventing refers to reducing the likelihood of herpesvirus infection.
  • alkyl refers to an aliphatic hydrocarbon group having one of its hydrogen atoms replaced with a bond.
  • An alkyl group may be straight or branched and contain from about 1 to about 20 carbon atoms. In one embodiment, an alkyl group contains from about 1 to about 12 carbon atoms. In different embodiments, an alkyl group contains from 1 to 6 carbon atoms (C1-C6 alkyl) or from about 1 to about 4 carbon atoms (C1-C4 alkyl).
  • Non limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, neopentyl, isopentyl, n-hexyl, isohexyl and neohexyl.
  • An alkyl group may be unsubstituted or substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkenyl, alkynyl, aryl, cycloalkyl, cyano, hydroxy, -O-alkyl, -O-aryl, -alkylene-O-alkyl, alkylthio, -NH2, -NH(alkyl), -N(alkyl)2, NH(cycloalkyl), -0-C(0)-alkyl, -0-C(0)-aryl, -O-C(O)- cycloalkyl, -C(0)OH and -C(0)0-alkyl.
  • an alkyl group is linear.
  • an alkyl group is branched. Unless otherwise indicated, an alkyl group is unsubstituted.
  • alkenyl refers to an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and having one of its hydrogen atoms replaced with a bond.
  • An alkenyl group may be straight or branched and contain from about 2 to about 15 carbon atoms. In one embodiment, an alkenyl group contains from about 2 to about 12 carbon atoms.
  • an alkenyl group contains from about 2 to about 6 carbon atoms.
  • alkenyl groups include ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n- pentenyl, octenyl and decenyl.
  • An alkenyl group may be unsubstituted or substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkenyl, alkynyl, aryl, cycloalkyl, cyano, hydroxy, - O-alkyl, -O-aryl, -alkylene-O-alkyl, alkylthio, -NH2, -NH(alkyl), -N(alkyl)2, -NH(cycloalkyl), - 0-C(0)-alkyl, -0-C(0)-aryl, -0-C(0)-cycloalkyl, -C(0)OH and -C(0)0-alkyl.
  • C2- Ce alkenyl refers to an alkenyl group having from 2 to 6 carbon atoms. Unless otherwise indicated, an alkenyl group is unsubstituted.
  • alkynyl refers to an aliphatic hydrocarbon group containing at least one carbon-carbon triple bond and having one of its hydrogen atoms replaced with a bond.
  • An alkynyl group may be straight or branched and contain from about 2 to about 15 carbon atoms. In one embodiment, an alkynyl group contains from about 2 to about 12 carbon atoms.
  • an alkynyl group contains from about 2 to about 6 carbon atoms.
  • alkynyl groups include ethynyl, propynyl, 2-butynyl and 3-methylbutynyl.
  • An alkynyl group may be unsubstituted or substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkenyl, alkynyl, aryl, cycloalkyl, cyano, hydroxy, -O-alkyl, -O-aryl, -alkylene-O-alkyl, alkylthio, -NH2, -NH(alkyl), -N(alkyl)2, -NH(cycloalkyl), -0-C(0)-alkyl, -0-C(0)-aryl, -O- C(0)-cycloalkyl, -C(0)0H and -C(0)0-alkyl.
  • C2-C6 alkynyl refers to an alkynyl group having from 2 to 6 carbon atoms. Unless otherwise indicated, an alkynyl group is unsubstituted.
  • alkylene refers to an alkyl group, as defined above, wherein one of the alkyl group’s hydrogen atoms has been replaced with a bond.
  • alkylene groups include -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, - CH(CH3)CH2CH2-, -CH(CH3)- and -CH2CH(CH3)CH2-.
  • an alkylene group has from 1 to about 6 carbon atoms.
  • an alkylene group is branched.
  • an alkylene group is linear.
  • an alkylene group is - CH2-.
  • C1-C6 alkylene refers to an alkylene group having from 1 to 6 carbon atoms.
  • aryl refers to an aromatic monocyclic or multicyclic ring system comprising from about 6 to about 14 carbon atoms. In one embodiment, an aryl group contains from about 6 to about 10 carbon atoms. An aryl group can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein below. In one embodiment, an aryl group can be optionally fused to a cycloalkyl or cycloalkanoyl group. Non-limiting examples of aryl groups include phenyl and naphthyl. In one embodiment, an aryl group is phenyl. In another embodiment, an aryl group is napthalene. Unless otherwise indicated, an alkyl group is unsubstituted.
  • cycloalkyl refers to a non-aromatic mono- or multicyclic ring system comprising from about 3 to about 10 ring carbon atoms. In one embodiment, a cycloalkyl contains from about 5 to about 10 ring carbon atoms. In another embodiment, a cycloalkyl contains from about 3 to about 7 ring atoms. In another embodiment, a cycloalkyl contains from about 5 to about 6 ring atoms.
  • monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • Non- limiting examples of multicyclic cycloalkyls include 1-decabnyl, norbomyl and adamantyl.
  • a cycloalkyl group can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein below. Unless otherwise indicated, an alkynyl group is unsubstituted. In one embodiment, a cycloalkyl group is unsubstituted.
  • the term “3 to 6-membered cycloalkyl” refers to a cycloalkyl group having from 3 to 6 ring carbon atoms. A ring carbon atom of a cycloalkyl group may be functionalized as a carbonyl group.
  • An illustrative example of such a cycloalkyl group (also referred to herein as a “cycloalkanoyl” group) includes, but is not limited to, cyclobutanoyl:
  • cycloalkenyl refers to anon-aromatic mono- or multi cyclic ring system comprising from about 4 to about 10 ring carbon atoms and containing at least one endocycbc double bond. In one embodiment, a cycloalkenyl contains from about 4 to about 7 ring carbon atoms. In another embodiment, a cycloalkenyl contains 5 or 6 ring atoms.
  • monocyclic cycloalkenyls include cyclopentenyl, cyclohexenyl, cyclohepta-l,3-dienyl, and the like.
  • a cycloalkenyl group can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein below.
  • a ring carbon atom of a cycloalkyl group may be functionalized as a carbonyl group.
  • a cycloalkenyl group is cyclopentenyl.
  • a cycloalkenyl group is cyclohexenyl.
  • the term “4 to 6-membered cycloalkenyl” refers to a cycloalkenyl group having from 4 to 6 ring carbon atoms.
  • halo means -F, -Cl, -Br or -I.
  • haloalkyl refers to an alkyl group as defined above, wherein one or more of the alkyl group’s hydrogen atoms has been replaced with a halogen.
  • a haloalkyl group has from 1 to 6 carbon atoms.
  • a haloalkyl group is substituted with from 1 to 3 F atoms.
  • Non-limiting examples of haloalkyl groups include -CFkF, -CHF2, -CF3, -CH2CI and -CCI3.
  • C1-C6 haloalkyl refers to a haloalkyl group having from 1 to 6 carbon atoms.
  • hydroxyalkyl refers to an alkyl group as defined above, wherein one or more of the alkyl group’s hydrogen atoms has been replaced with an -OH group.
  • a hydroxyalkyl group has from 1 to 6 carbon atoms.
  • Non-limiting examples of hydroxyalkyl groups include -CH2OH, -CH2CH2OH, -CH2CH2CH2OH and - CH2CH(OH)CH3.
  • C1-C6 hydroxyalkyl refers to a hydroxyalkyl group having from 1 to 6 carbon atoms.
  • heteroaryl refers to an aromatic monocyclic or multicyclic ring system comprising about 5 to about 14 ring atoms, wherein from 1 to 4 of the ring atoms is independently O, N or S and the remaining ring atoms are carbon atoms.
  • a heteroaryl group has 5 to 10 ring atoms.
  • a heteroaryl group is monocyclic and has 5 or 6 ring atoms.
  • a heteroaryl group is bicyclic and had 9 or 10 ring atoms.
  • a heteroaryl group can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein below.
  • heteroaryl group is joined via a ring carbon atom, and any nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide.
  • heteroaryl also encompasses a heteroaryl group, as defined above, which is fused to a benzene ring.
  • heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone (including N- substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl, imidazo[l,2-a]pyridinyl, imidazo[2,l-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, benzimidazolyl, thienopyr
  • heteroaryl also refers to partially saturated heteroaryl moieties such as, for example, tetrahydroisoquinolyl, tetrahydroquinolyl and the like.
  • a heteroaryl group is a 5-membered heteroaryl.
  • a heteroaryl group is a 6-membered heteroaryl.
  • a “9- or 10-membered bicyclic heteroaryl” group comprises a 5- to 6-membered heterocycloalkyl group fused to a benzene ring, such as:
  • a “9- or 10-membered bi cyclic heteroaryl” group comprises a 5- to 6-membered heteroaryl group fused to a cycloalkyl ring or a heterocycloalkyl ring, such as:
  • heteroarylene refers to a bivalent group derived from an heteroaryl group, as defined above, by removal of a hydrogen atom from a ring carbon or ring heteroatom of a heteroaryl group.
  • a heteroarylene group can be derived from a monocyclic or multi cyclic ring system comprising about 5 to about 14 ring atoms, wherein from 1 to 4 of the ring atoms are each independently O, N or S and the remaining ring atoms are carbon atoms.
  • a heteroarylene group can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein below.
  • heteroarylene group is joined via a ring carbon atom or by a nitrogen atom with an open valence, and any nitrogen atom of a heteroarylene can be optionally oxidized to the corresponding N-oxide.
  • heteroarylene also encompasses a heteroarylene group, as defined above, which is fused to a benzene ring.
  • heteroarylenes include pyridylene, pyrazinylene, furanylene, thienylene, pyrimidinylene, pyridonylene (including those derived from N- substituted pyridonyls), isoxazolylene, isothiazolylene, oxazolylene, oxadiazolylene, thiazolylene, pyrazolylene, thiophenylene, furazanylene, pyrrolylene, triazolylene, 1,2,4- thiadiazolylene, pyrazinylene, pyridazinylene, quinoxalinylene, phthalazinylene, oxindolylene, imidazo[l,2-a]pyridinylene, imidazo[2,l-b]thiazolylene, benzofurazanylene, indolylene, azaindolylene, benzimidazolylene, benzothienylene, quinolinylene, imidazolylene
  • heteroarylene also refers to partially saturated heteroarylene moieties such as, for example, tetrahydroisoquinolylene, tetrahydroquinolylene, and the like.
  • a heteroarylene group is divalent and unless specified ohterwise, either available bond on a heteroarylene ring can connect to either group flanking the heteroarylene group.
  • the group “A-heteroarylene-B,” wherein the heteroarylene group is: is understood to represent both:
  • a heteroarylene group is a monocyclic heteroarylene group or a bicyclic heteroarylene group. In another embodiment, a heteroarylene group is a monocyclic heteroarylene group. In another embodiment, a heteroarylene group is a bi cyclic heteroarylene group. In still another embodiment, a heteroarylene group has from about 5 to about 10 ring atoms. In another embodiment, a heteroarylene group is monocyclic and has 5 or 6 ring atoms.
  • a heteroarylene group is bicyclic and has 9 or 10 ring atoms.
  • a heteroarylene group is a 5-membered monocyclic heteroarylene.
  • a heteroarylene group is a 6-membered monocyclic heteroarylene.
  • a bicyclic heteroarylene group comprises a 5 or 6-membered monocyclic heteroarylene group fused to a benzene ring.
  • a heteroaryl group comprises a 5- to 6-membered monocyclic heteroarylene group fused to a cycloalkyl ring or a heterocycloalkyl ring.
  • heterocycloalkyl refers to anon-aromatic saturated monocyclic or multicyclic ring system comprising 3 to about 11 ring atoms, wherein from 1 to 4 of the ring atoms are independently O, S, N or Si, and the remainder of the ring atoms are carbon atoms.
  • a heterocycloalkyl group can be joined via a ring carbon, ring silicon atom or ring nitrogen atom.
  • a heterocycloalkyl group is monocyclic and has from about 3 to about 7 ring atoms.
  • a heterocycloalkyl group is monocyclic has from about 4 to about 7 ring atoms.
  • a heterocycloalkyl group is bicyclic and has from about 7 to about 11 ring atoms. In still another embodiment, a heterocycloalkyl group is monocyclic and has 5 or 6 ring atoms. In one embodiment, a heterocycloalkyl group is monocyclic. In another embodiment, a heterocycloalkyl group is bicyclic. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Any -NH group in a heterocycloalkyl ring may exist protected such as, for example, as an -N(BOC), -N(CBz), -N(Tos) group and the like; such protected heterocycloalkyl groups are considered part of this invention.
  • a heterocycloalkyl group can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein below.
  • the nitrogen or sulfur atom of the heterocycloalkyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
  • Non-limiting examples of monocyclic heterocycloalkyl rings include oxetanyl, piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1 ,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, delta-lactam, delta-lactone, silacyclopentane, silapyrrolidine and the like, and all isomers thereof.
  • Non-limiting illustrative examples of a silyl-containing heterocycloalkyl group include:
  • a ring carbon atom of a heterocycloalkyl group may be functionalized as a carbonyl group.
  • Illustrative examples of such a heterocycloalkyl group include, but are not limited to:
  • a ring sulfur atom of a heterocycloalkyl group may also be functionalized as a sulfonyl group.
  • An example of such a heterocycloalkyl group is:
  • a heterocycloalkyl group is a 5-membered monocyclic heterocycloalkyl. In another embodiment, a heterocycloalkyl group is a 6-membered monocyclic heterocycloalkyl.
  • the term “5- to 7-membered monocyclic cycloalkyl” refers to a monocyclic heterocycloalkyl group having from 5 to 5 ring atoms.
  • the term “4 to 6-membered monocyclic cycloalkyl” refers to a monocyclic heterocycloalkyl group having from 4 to 6 ring atoms.
  • the term “9 to 10-membered bicyclic heterocycloalkyl” refers to a bicyclic heterocycloalkyl group having from 9 to 10 ring atoms.
  • heterocycloalkenyl refers to a heterocycloalkyl group, as defined above, wherein the heterocycloalkyl group contains from 4 to 10 ring atoms, and at least one endocyclic carbon-carbon or carbon-nitrogen double bond.
  • a heterocycloalkenyl group can be joined via a ring carbon or ring nitrogen atom.
  • a heterocycloalkenyl group has from 4 to 6 ring atoms.
  • a heterocycloalkenyl group is monocyclic and has 5 or 6 ring atoms.
  • a heterocycloalkenyl group is bicyclic.
  • a heterocycloalkenyl group can optionally substituted by one or more ring system substituents, wherein "ring system substituent" is as defined above.
  • the nitrogen or sulfur atom of the heterocycloalkenyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
  • a ring carbon atom of a heterocycloalkenyl group may be functionalized as a carbonyl group.
  • heterocycloalkenyl groups include 1, 2,3,4- tetrahydropyridinyl, 1 ,2-dihydropyridinyl, 1,4-dihydropyridinyl, 1,2,3,6-tetrahydropyridinyl, 1,4,5,6-tetrahydropyrimidinyl, 2-pyrrobnyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazobnyl, dihydroimidazolyl, dihydrooxazolyl, dihydrooxadiazolyl, dihydrothiazolyl, 3,4-dihydro-2H- pyranyl, dihydrofuranyl, fluoro-substituted dihydrofuranyl, 7-oxabicyclo[2.2.1]heptenyl, dihydrothiophenyl, dihydrothiopyranyl, and the like and the like.
  • a heterocycloalkenyl group is a 5-membered heterocycloalkenyl. In another embodiment, a heterocycloalkenyl group is a 6-membered heterocycloalkenyl.
  • the term “4 to 6-membered heterocycloalkenyl” refers to a heterocycloalkenyl group having from 4 to 6 ring atoms.
  • substituted means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom’s normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • stable compound or “stable structure” is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • substantially purified form refers to the physical state of a compound after the compound is isolated from a synthetic process (e.g., from a reaction mixture), a natural source, or a combination thereof.
  • substantially purified form also refers to the physical state of a compound after the compound is obtained from a purification process or processes described herein or well-known to the skilled artisan (e.g., chromatography, recrystallization and the like), in sufficient purity to be characterizable by standard analytical techniques described herein or well-known to the skilled artisan.
  • protecting groups When a functional group in a compound is termed “protected”, this means that the group is in modified form to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as, for example, T. W. Greene et al, Protective Groups in Organic Synthesis (1991), Wiley, New York.
  • ring system substituents include, but are not limited to, alkyl, alkenyl, alkynyl, aryl, heteroaryl, -alkylene-aryl, -arylene-alkyl, -alkylene-heteroaryl,-alkenylene-heteroaryl, -alkynylene-heteroaryl, -OH, hydroxyalkyl, haloalkyl, -O-alkyl, -O-haloalkyl, -alkylene-O-alkyl, -O-aryl, -O-alkylene-aryl, acyl, - C(O)- aryl, halo, -NO2, -CN, -SFs, -C(0)0H, -C(0)0-alkyl, -C(0)0-aryl, -C(0)0-alkylene-aryl, - S(0)-alkyl, -S(0)2-alkyl, -S(0)-aryl,
  • Ring system substituent may also mean a single moiety which simultaneously replaces two available hydrogens on two adjacent carbon atoms (one H on each carbon) on a ring system. Examples of such moiety are methylenedioxy, ethylenedioxy, -C(CH3)2- and the like which form moieties such as, for example:
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results from combination of the specified ingredients in the specified amounts.
  • Prodrugs and solvates of the compounds of the invention are also contemplated herein. A discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press.
  • prodrug means a compound (e.g., a drug precursor) that is transformed in vivo to provide an Amido-Substituted Heterocyclic Compound or a pharmaceutically acceptable salt or solvate of the compound.
  • the transformation may occur by various mechanisms (e.g., by metabolic or chemical processes), such as, for example, through hydrolysis in blood.
  • a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as, for example, (Ci-C8)alkyl, (C2-Ci2)alkanoyloxymethyl, 1- (alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1 -methyl- l-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1- (alkoxycarbonyloxy)ethyl having from 4 to 6 carbon atoms, 1 -methyl- 1- (alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms,
  • a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as, for example, (Ci-C6)alkanoyloxymethyl, l-((Ci- C6)alkanoyloxy)ethyl, 1 -methyl- 1 -((C i-C6)alkanoyloxy)ethyl, (C i-C6)alkoxy carbonyloxymethyl, N-(Ci-C6)alkoxycarbonylaminomethyl, succinoyl, (Ci-CT)alkanoyl.
  • a group such as, for example, (Ci-C6)alkanoyloxymethyl, l-((Ci- C6)alkanoyloxy)ethyl, 1 -methyl- 1 -((C i-C6)alkanoyloxy)ethyl, (C i-C6)alkoxy carbonyloxymethyl, N-(Ci-C6)alkoxycarbonylaminomethyl,
  • a-amino(Ci-C4)alkyl a- amino(Ci-C4)alkylene-aryl, arylacyl and a-aminoacyl, or a-aminoacyl-a-aminoacyl, where each a-aminoacyl group is independently selected from the naturally occurring L-amino acids, - P(0)(OH)2, -P(0)(0(Ci-C6)alkyl)2 or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate), and the like.
  • a prodrug can be formed by the replacement of a hydrogen atom in the amine group with a group such as, for example, R-carbonyl-, RO-carbonyl-, NRR’ -carbonyl- wherein R and R’ are each independently (Ci-Cio)alkyl, (C3-C7) cycloalkyl, benzyl, a natural a-aminoacyl, - C(0H)C(0)0Y 1 wherein Y 1 is H, (Ci-CT)alkyl or benzyl, -C(OY 2 )Y 3 wherein Y 2 is (C1-C4) alkyl and Y 3 is (Ci-C6)alkyl; carboxy (Ci-C6)alkyl; amino(Ci-C4)alkyl or mono-N- or di-N,N-(Ci- C6)alkylaminoalky
  • esters of the present compounds include the following groups: (1) carboxylic acid esters obtained by esterification of the hydroxy group of a hydroxyl compound, in which the non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl (e.g ., methyl, ethyl, n-propyl, isopropyl, t-butyl, sec-butyl orn-butyl), alkoxyalkyl (e.g., methoxymethyl), aralkyl (e.g., benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (e.g., phenyl optionally substituted with, for example, halogen, Cmalkyl, -0-(Ci-4alkyl) or amino); (2) sulfonate esters, such as alkyl- or aralkylsulfonyl (for example, methanesulf
  • One or more compounds of the invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms.
  • “Solvate” means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate” encompasses both solution-phase and isolatable solvates. Non-limiting examples of solvates include ethanolates, methanolates, and the like. A “hydrate” is a solvate wherein the solvent molecule is water.
  • One or more compounds of the invention may optionally be converted to a solvate.
  • Preparation of solvates is generally known.
  • M. Caira et al, J. Pharmaceutical Sci., 93(3), 601-611 (2004) describe the preparation of the solvates of the antifungal fluconazole in ethyl acetate as well as from water.
  • Similar preparations of solvates, hemisolvate, hydrates and the like are described by E. C. van Tonder et al, AAPS PharmSciTechours. , 5(1), article 12 (2004); and A. L. Bingham et al, Chem. Commun., 603-604 (2001).
  • a typical, non-limiting, process involves dissolving the inventive compound in desired amounts of the desired solvent (organic or water or mixtures thereof) at a higher than room temperature, and cooling the solution at a rate sufficient to form crystals which are then isolated by standard methods.
  • Analytical techniques such as, for example IR spectroscopy, show the presence of the solvent (or water) in the crystals as a solvate (or hydrate).
  • the Amido-Substituted Heterocyclic Compounds can form salts which are also within the scope of this invention.
  • the term "salt(s)" denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases.
  • an Amido-Substituted Heterocyclic Compound contains both a basic moiety, such as, but not limited to a pyridine or imidazole, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions ("inner salts”) may be formed and are included within the term "salt(s)" as used herein.
  • the salt is a pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salt.
  • the salt is other than a pharmaceutically acceptable salt.
  • Salts of the Compounds of Formula (I) may be formed, for example, by reacting an Amido-Substituted Heterocyclic Compound with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
  • Exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates), and the like.
  • Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamine, t-butyl amine, choline, and salts with amino acids such as arginine, lysine and the like.
  • alkali metal salts such as sodium, lithium, and potassium salts
  • alkaline earth metal salts such as calcium and magnesium salts
  • salts with organic bases for example, organic amines
  • organic bases for example, organic amines
  • amino acids such as arginine, lysine and the like.
  • Basic nitrogen-containing groups may be quartemized with agents such as lower alkyl halides (e.g., methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, and dibutyl sulfates), long chain halides (e.g., decyl, lauryl, and stearyl chlorides, bromides and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and others.
  • lower alkyl halides e.g., methyl, ethyl, and butyl chlorides, bromides and iodides
  • dialkyl sulfates e.g., dimethyl, diethyl, and dibutyl sulfates
  • long chain halides e.g., decyl, lauryl,
  • Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well-known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization.
  • Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher’s acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers.
  • an appropriate optically active compound e.g., chiral auxiliary such as a chiral alcohol or Mosher’s acid chloride
  • Sterochemically pure compounds may also be prepared by using chiral starting materials or by employing salt resolution techniques.
  • Amido-Substituted Heterocyclic Compounds may be atropisomers (e.g., substituted biaryls), and are considered as part of this invention. Enantiomers can also be directly separated using chiral chromatographic techniques.
  • Amido-Substituted Heterocyclic Compounds may exist in different tautomeric forms, and all such forms are embraced within the scope of the invention.
  • all keto-enol and imine-enamine forms of the compounds are included in the invention.
  • All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds including those of the salts, solvates, hydrates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention. If an Amido- Substituted Heterocyclic Compound incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention.
  • Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers.
  • the chiral centers of the present invention can have the S or R configuration as defined by the I UP AC 1974 Recommendations.
  • the use of the terms "salt”, “solvate”, “ester”, “prodrug” and the like, is intended to apply equally to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs of the inventive compounds.
  • the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature.
  • the present invention is meant to include all suitable isotopic variations of the compounds of generic Formula I.
  • different isotopic forms of hydrogen (H) include protium (3 ⁇ 4), and deuterium ( 2 H).
  • Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples.
  • Isotopically-enriched Compounds of Formula (I) can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and/or intermediates.
  • a Compound of Formula (I) has one or more of its hydrogen atoms replaced with deuterium.
  • Polymorphic forms of the Amido-Substituted Heterocyclic Compounds, and of the salts, solvates, hydrates, esters and prodrugs of the Amido-Substituted Heterocyclic Compounds, are intended to be included in the present invention.
  • DMAP is M-V-dimethylami nopyridine: ESI is electrospray ionization; HPLC is high performance liquid chromatography; (Ir[DF(CF3)PPY]2(DTBPY))PF6 is
  • the present invention provides Amido-Substituted Heterocyclic Compounds of Formula
  • X is selected from groups (a), (b), and (c).
  • X is: In another embodiment, for the Compounds of formula (I), X is:
  • R 5 represents 1 or 2 phenyl substituents, each independently selected from F, Cl, -CN, -CF3, -CH2OH, -CH2N(CH3)2, - CH2OCH3, and -CFh-O-benzyl.
  • X is: and R 5 is Cl or -CN.
  • X is and R 5 is Cl or -CN.
  • X is and R 5 is Cl or -CN.
  • X is selected from:
  • R 1 is H.
  • R 1 is -OR 7 .
  • R 1 is methoxy.
  • R 2 is:
  • R 2 is:
  • R 3 is H.
  • R 4 is H.
  • R 5 is selected from halo and -CN. In another embodiment, for the compounds of formula (I), R 5 is Cl.
  • R 5 is CN
  • R 5 is 4-Cl or 4-CN.
  • R 5 is 4-Cl.
  • R 6 is H.
  • R 6 is halo. In another embodiment, for the compounds of formula (I), R 6 is F.
  • the compounds of formula (I) have the formula (la): or a pharmaceutically acceptable salt thereof, wherein:
  • R 1 is H or -0-(Ci-C6 alkyl).
  • R 5 represents 1 or 2 phenyl substituents, each independently selected from Cl, - CN, -CF 3 , -CH2OH, -CH 2 N(CH 3 ) 2 , -CH 2 OCH 3 , and -CH 2 -0-benzyl.
  • R 1 is H.
  • R 1 is methoxy
  • R 5 is 4-Cl or 4-CN.
  • composition comprising an effective amount of a Compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • composition of (b), wherein the anti-herpes agent is selected from the group consisting of herpesvirus polymerase inhibitors, and CMV terminase inhibitors.
  • a pharmaceutical combination that is (i) a Compound of Formula (I), and (ii) a second therapeutic agent selected from the group consisting of anti-herpes agents and immunomodulators; wherein the Compound of Formula (I), and the second therapeutic agent are each employed in an amount that renders the combination effective for inhibiting herpesvirus replication, or for treating herpesvirus infection and/or reducing the likelihood or severity of symptoms of herpesvirus infection.
  • a method of inhibiting herpesvirus replication in a subject in need thereof which comprises administering to the subject an effective amount of a Compound of Formula (I).
  • a method of treating herpesvirus infection and/or reducing the likelihood or severity of symptoms of herpesvirus infection in a subject in need thereof which comprises administering to the subject an effective amount of a Compound of Formula (I).
  • a method of inhibiting herpesvirus replication in a subject in need thereof which comprises administering to the subject the pharmaceutical composition of (a), (b) or (c) or the combination of (d) or (e).
  • (k) A method of treating herpesvirus infection and/or reducing the likelihood or severity of symptoms of herpesvirus infection in a subject in need thereof which comprises administering to the subject the pharmaceutical composition of (a), (b) or (c) or the combination of (d) or (e).
  • the present invention also includes a compound of the present invention for use (i) in,
  • the compounds of the present invention can optionally be employed in combination with one or more second therapeutic agents selected from anti-herpes agents, anti-infective agents, and immunomodulators.
  • Additional embodiments of the invention include the pharmaceutical compositions, combinations and methods set forth in (a)-(k) above and the uses set forth in the preceding paragraph, wherein the compound of the present invention employed therein is a compound of one of the embodiments, aspects, classes, sub-classes, or features of the compounds described above. In all of these embodiments, the compound may optionally be used in the form of a pharmaceutically acceptable salt or hydrate as appropriate.
  • compositions and methods provided as (a) through (k) above are understood to include all embodiments of the compounds, including such embodiments as result from combinations of embodiments.
  • Non-limiting examples of the Compounds of Formula (I) include compounds 1-36, as set forth in the Examples below, and pharmaceutically acceptable salts thereof.
  • the Compounds of Formula (I) may be prepared from known or readily prepared starting materials, following methods known to one skilled in the art of organic synthesis. Methods useful for making the Compounds of Formula (I) are set forth in the Examples below Alternative synthetic pathways and analogous structures will be apparent to those skilled in the art of organic synthesis.
  • the starting materials used and the intermediates prepared using the methods set forth in the Examples below may be isolated and purified if desired using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography and alike.
  • Such materials can be characterized using conventional means, including physical constants and spectral data.
  • Step A synthesis of compound lb To a mixture of compound la (100 mL) was added lithium bis(trimethylsilyl)amide (108 mL, 108 mmol) (1 M in tetrahydrofuran) at 0 °C under nitrogen atmosphere. The resulting reaction was allowed to stir for 5 minutes at 0 °C. di-tert- butyl dicarbonate (12.01 mL, 51.7 mmol) was then added and the resulting reaction was allowed to stir at 0 °C for 2 hours. The reaction was quenched with saturated aqueous ammonium chloride (200 mL), and extracted with ethyl acetate (3 x 200 mL).
  • the resulting reaction was irradiated with blue LED (400 nm, 15 W) for 16 hours at room temperature under argon atmosphere.
  • the reaction was quenched with water (20 mL), and extracted with ethyl acetate (3 x 30 mL).
  • the combined organic extracts were washed with saturated aqueous sodium chloride (3 x 30 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo.
  • the residue obtained was purified using silica gel column chromatography, eluting with a gradient of methanol :dichloromethane - 1: 100 to 1:10 to provide compound lc.
  • Step A synthesis of compound 2b To a mixture of methyl 2-(2-bromo-4-chlorophenyl)acetate (2a, 1.7 g, 6.45 mmol), caesium carbonate (7.6 g, 23.22 mmol), methanesulfonato(2-dicyclohexylphosphino-2',6'- ⁇ i/-/- propoxy-l,r-biphenyl)(2'-amino-l,r-biphenyl-2-yl)palladium(II) (0.5 g, 0.645 mmol) in toluene (50 mL), and water (5 mL) at room temperature under nitrogen atmosphere, was added potassium benzyloxymethyltrifluoroborate (2.2 g, 9.68 mmol).
  • the reaction mixture was irradiated with blue LED (400 nm, 15 W), for 1 hour at room temperature under argon atmosphere.
  • the reaction was quenched with water (5 mL), and extracted with ethyl acetate (3 x 10 mL).
  • the combined organic extracts were washed with saturated aqueous sodium chloride (10 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo.
  • the residue obtained was purified using preparative HPLC, eluting with a gradient of acetonitrile: 20 mM aq. ammonium bicarbonate - 1:19 to 3:2 to provide compound 4 as a solid.
  • the resulting reaction was irradiated with blue LED (400 nm, 15 W) for 16 hours at room temperature under argon atmosphere.
  • the reaction mixture was diluted with water (100 mL), and extracted with ethyl acetate (3 c 100 mL).
  • the combined organic extracts were washed with saturated aqueous sodium chloride (100 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo.
  • MRC5 and Vero cells were obtained from ATCC and were maintained at 37°C/5% CC /90% relative humidity in Minimal Essential Medium with 10% fetal bovine serum, 2.0 nM
  • Assay plates were prepared by dispensing compounds dissolved in DMSO into wells of 384 well collagen-coated plates using an ECHO acoustic dispenser. Each test compound was tested in a 10-point, serial 3 -fold dilution. Controls included uninfected cells and infected cells treated only with DMSO. Assays were initiated by mixing selected cells, in suspension, with virus, and dispensing 50pl/well infected cells to pre-plated compounds.
  • lysis buffer lOmM Tris-HCl, pH8, 50mM KC1, 2mM MgCh. 0.45% NP-40, 0.45% Tween-20, and 100pg/mL proteinase K. An aliquot of the lysate was then transferred to a 384-well PCR plate and incubated at 56 °C for 1 hour, and then at 95 °C for 10 minutes.
  • HSV-1 Strain F was assayed in Vero or MRC5 cells and was used at 0.0005-0.004 pfu/cell in growth medium.
  • Human cytomegalovirus and varicella zoster virus DNA polymerases were expressed via baculovirus vector in SF21 cells and purified.
  • Heterodimeric nucleic acid substrate used in the herpesvirus polymerase reactions were generated by annealing a 59-mer template to a 17-mer digoxigenin-labeled primer.
  • Polymerase (HCMV final concentration of 0.2nM; VZV final concentration of 0.4nM) was combined with an inhibitor compound or DMSO in assay buffer (10 mM HEPES, pH 7.5, 25 mM KC1, 25 mM NaCl, 5 mM MgCh, 5% glycerol, 0.67 mg/ml bovine serum albumin, and ImM tris(2-carboxyethyl)phosphine)), and this mixture was pre incubated for 30 minutes at room temperature in 384-well microtiter plates.
  • assay buffer 10 mM HEPES, pH 7.5, 25 mM KC1, 25 mM NaCl, 5 mM MgCh, 5% glycerol, 0.67 mg/ml bovine serum albumin, and ImM tris(2-carboxyethyl)phosphine
  • the polymerization reaction was initiated by the addition of template/primer substrate (final concentration: 1.6 nM) and dNTPs (final concentration: 24 nM dCTP, 24 nMdGTP, 16nM dATP, 16 nM dTTP, and 0.8nM biotin-dUTP). After a 60 minute incubation period at 37°C, the reactions were terminated using quench buffer (25 mM HEPES pH 7.5, 100 mM NaCl, 0.25% Tween-20, 12 mM EDTA, and lmg/ml bovine serum albumin).
  • quench buffer 25 mM HEPES pH 7.5, 100 mM NaCl, 0.25% Tween-20, 12 mM EDTA, and lmg/ml bovine serum albumin.
  • the Amido-Substituted Heterocyclic Compounds are useful in human and veterinary medicine for treating or preventing a viral infection in a patient.
  • the Amido- Substituted Heterocyclic Compounds can be inhibitors of viral replication.
  • the Amido-Substituted Heterocyclic Compounds can be inhibitors of herpesvirus replication. Accordingly, the Amido-Substituted Heterocyclic Compounds are useful for treating viral infections, such as herpesvirus.
  • the Amido-Substituted Heterocyclic Compounds can be administered to a patient in need of treatment or prevention of a viral infection.
  • the invention provides methods for treating or preventing a viral infection in a patient comprising administering to the patient an effective amount of at least one Amido-Substituted Heterocyclic Compound or a pharmaceutically acceptable salt thereof.
  • the Amido-Substituted Heterocyclic Compounds are useful in the inhibition of herpesvirus replication, the treatment of herpesvirus infection and/or reduction of the likelihood or severity of symptoms of herpesvirus infection and the inhibition of herpesvirus viral replication and/or herpesvirus viral production in a cell-based system.
  • the Amido- Substituted Heterocyclic Compounds are useful in treating infection by herpesvirus after suspected past exposure to herpesvirus by such means as blood transfusion, exchange of body fluids, bites, accidental needle stick, or exposure to patient blood during surgery or other medical procedures.
  • the invention provides a method for treating herpesvirus infection in a patient, the method comprising administering to the patient an effective amount of at least one Amido-Substituted Heterocyclic Compound or a pharmaceutically acceptable salt thereof.
  • the herpesvirus being treated or prevented is of the family a- herpesviridae.
  • Herpesviruses of the family a-herpesviridae include, but are not limited to, herpes simplex virus 1 (HSV-1), herpes simplex 2 (HSV-2), and varicella zoster virus (VZV).
  • the herpesvirus being treated or prevented is of the family b- herpesviridae.
  • Herpesviruses of the family b-herpesviridae include, but are not limited to, human cytomegalovirus (CMV), human herpesvirus 6 (HHV6), and human herpesvirus 7 (HHV7).
  • the herpesvirus being treated or prevented is of the family g- herpesviridae.
  • Herpesviruses of the family g-herpesviridae include, but are not limited to, Epstein-Barr virus (EBV), human herpesvirus 4 (HHV4), and Kaposi’s sarcoma-associated herpesvirus (KHSV), also known as human herpesvirus 8 (HHV8).
  • the herpesvirus being treated or prevented is HSV-1.
  • the herpesvirus being treated or prevented is HSV-2.
  • the herpesvirus being treated or prevented is VZV.
  • the herpesvirus being treated or prevented is CMV.
  • the herpesvirus being treated or prevented is HHV6.
  • the herpesvirus being treated or prevented is HHV7.
  • the herpesvirus being treated or prevented is EBV.
  • the herpesvirus being treated or prevented is HHV4.
  • the herpesvirus being treated or prevented is KSHV.
  • the amount administered is effective to treat or prevent infection by herpesvirus in the patient. In another specific embodiment, the amount administered is effective to inhibit herpesvirus viral replication and/or viral production in the patient.
  • the Amido-Substituted Heterocyclic Compounds are also useful in the preparation and execution of screening assays for antiviral compounds. Furthermore, the Amido-Substituted Heterocyclic Compounds are useful in establishing or determining the binding site of other antivirals to the herpesvirus polymerase.
  • compositions and combinations of the present invention can be useful for treating a patient suffering from infection related to any herpesvirus infection.
  • Herpesvirus types may differ in their antigenicity, level of viremia, severity of disease produced, and response to therapy. See Poole etal., Clinical Therapeutics, 40:8 (2016), 1282-1298.
  • the present methods for treating or preventing herpesvirus infection can further comprise the administration of one or more additional therapeutic agents which are not Amido-Substituted Heterocyclic Compounds.
  • the additional therapeutic agent is an antiviral agent. In another embodiment, the additional therapeutic agent is an anti-herpes agent.
  • Anti-herpes agents useful in the present compositions and methods include, but are not limited to, nucleoside polymerase inhibitors, such as acyclovir, valaciclovir, famciclovir, penciclovir, cidofovir, brincidofovir (CMX-001), valmanciclovir, ganciclovir, valganciclovir, and N-methanocarbathymidine (N-MCT); pyrophosphate polymerase inhibitors, such as foscamet; CMV terminase inhibitors, such as letermovir; viral kinase inhibitors, such as maribavir; and helicase-primase inhibitors, such as pritelivir (AIC-316) and amenamevir (ASP- 2151).
  • nucleoside polymerase inhibitors such as acyclovir, valaciclovir, famciclovir, penciclovir, cidofovir, brincidofovir (CMX-
  • the additional therapeutic agent is an immunomodulatory agent, such as an immunosuppressive agent.
  • Immunosuppressant agents useful in the present compositions and methods include, but are not limited to, cytotoxic agents, such as cyclophosphamide and cyclosporin A; corticosteroids, such as hydrocortisone and dexamethasone, and non-steroidal anti-inflammatory agents (NSAID).
  • the present invention provides methods for treating a herpesvirus infection in a patient, the method comprising administering to the patient: (i) at least one Amido-Substituted Heterocyclic Compound, or a pharmaceutically acceptable salt thereof, and (ii) at least one additional therapeutic agent that is other than an Amido-Substituted Heterocyclic Compound, wherein the amounts administered are together effective to treat or prevent the herpesvirus infection.
  • therapeutic agents in the combination may be administered in any order such as, for example, sequentially, concurrently, together, simultaneously and the like.
  • the amounts of the various actives in such combination therapy may be different amounts (different dosage amounts) or same amounts (same dosage amounts).
  • an Amido-Substituted Heterocyclic Compound and an additional therapeutic agent may be present in fixed amounts (dosage amounts) in a single dosage unit (e.g., a capsule, a tablet and the like).
  • the at least one Amido-Substituted Heterocyclic Compound is administered during a time when the additional therapeutic agent(s) exert their prophylactic or therapeutic effect, or vice versa.
  • the at least one Amido-Substituted Heterocyclic Compound and the additional therapeutic agent(s) are administered in doses commonly employed when such agents are used as monotherapy for treating a herpesvirus infection.
  • the at least one Amido-Substituted Heterocyclic Compound and the additional therapeutic agent(s) are administered in doses lower than the doses commonly employed when such agents are used as monotherapy for treating a herpesvirus infection.
  • the at least one Amido-Substituted Heterocyclic Compound and the additional therapeutic agent(s) act synergistically and are administered in doses lower than the doses commonly employed when such agents are used as monotherapy for treating a herpesvirus infection.
  • the at least one Amido-Substituted Heterocyclic Compound and the additional therapeutic agent(s) are present in the same composition.
  • this composition is suitable for oral administration.
  • this composition is suitable for intravenous administration.
  • this composition is suitable for subcutaneous administration.
  • this composition is suitable for parenteral administration.
  • the at least one Amido-Substituted Heterocyclic Compound and the additional therapeutic agent(s) can act additively or synergistically.
  • a synergistic combination may allow the use of lower dosages of one or more agents and/or less frequent administration of one or more agents of a combination therapy.
  • a lower dosage or less frequent administration of one or more agents may lower toxicity of therapy without reducing the efficacy of therapy.
  • the administration of at least one Amido-Substituted Heterocyclic Compound and the additional therapeutic agent(s) may inhibit the resistance of a herpesvirus infection to these agents.
  • the doses and dosage regimen of the other agents used in the combination therapies of the present invention for the treatment or prevention of herpesvirus infection can be determined by the attending clinician, taking into consideration the approved doses and dosage regimen in the package insert; the age, sex and general health of the patient; and the type and severity of the viral infection or related disease or disorder.
  • the Amido- Substituted Heterocyclic Compound(s) and the other agent(s) can be administered simultaneously (i.e., in the same composition or in separate compositions one right after the other) or sequentially.
  • kits comprising the separate dosage forms is therefore advantageous.
  • one or more compounds of the present invention are administered with one or more additional therapeutic agents selected from: an immunomodulator, an anti herpes agent, a viral replication inhibitor, an antisense agent, a therapeutic vaccine, a virion production inhibitor, a viral entry inhibitor, a viral assembly inhibitor, an antibody therapy (monoclonal or polyclonal), and any agent useful for treating any type of herpesvirus infection.
  • additional therapeutic agents selected from: an immunomodulator, an anti herpes agent, a viral replication inhibitor, an antisense agent, a therapeutic vaccine, a virion production inhibitor, a viral entry inhibitor, a viral assembly inhibitor, an antibody therapy (monoclonal or polyclonal), and any agent useful for treating any type of herpesvirus infection.
  • the Amido-Substituted Heterocyclic Compounds are useful in veterinary and human medicine. As described above, the Amido-Substituted Heterocyclic Compounds are useful for treating or preventing herpesvirus infection in a patient in need thereof.
  • the present invention provides pharmaceutical compositions comprising an effective amount of a compound of formula(I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the present invention provides pharmaceutical compositions comprising (i) an effective amount of a compound of formula(I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; and (ii) one or more additional therapeutic agents, wherein said additional therapeutic agents are selected from anti-herpes agents and immunomodulators.
  • the Amido-Substituted Heterocyclic Compounds can be administered as a component of a composition that comprises a pharmaceutically acceptable carrier or vehicle.
  • the present invention provides pharmaceutical compositions comprising an effective amount of at least one Amido-Substituted Heterocyclic Compound and a pharmaceutically acceptable carrier.
  • the active ingredients will typically be administered in admixture with suitable carrier materials suitably selected with respect to the intended form of administration, i.e., oral tablets, capsules (either solid-filled, semi-solid filled or liquid filled), powders for constitution, oral gels, elixirs, dispersible granules, syrups, suspensions, and the like, and consistent with conventional pharmaceutical practices.
  • suitable carrier materials suitably selected with respect to the intended form of administration, i.e., oral tablets, capsules (either solid-filled, semi-solid filled or liquid filled), powders for constitution, oral gels, elixirs, dispersible granules, syrups, suspensions, and the like, and consistent with conventional pharmaceutical practices.
  • the active drug component may be combined with any oral non-toxic pharmaceutically acceptable inert carrier, such as lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, talc, mannitol, ethyl alcohol (liquid forms) and the like.
  • Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. Powders and tablets may be comprised of from about 0.5 to about 95 percent inventive composition. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration.
  • suitable binders include starch, gelatin, natural sugars, com sweeteners, natural and synthetic gums such as acacia, sodium alginate, carboxymethylcellulose, polyethylene glycol and waxes.
  • lubricants there may be mentioned for use in these dosage forms, boric acid, sodium benzoate, sodium acetate, sodium chloride, and the like.
  • Disintegrants include starch, methylcellulose, guar gum, and the like. Sweetening and flavoring agents and preservatives may also be included where appropriate.
  • Liquid form preparations include solutions, suspensions and emulsions and may include water or water-propylene glycol solutions for parenteral or intravenous injection.
  • solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration.
  • liquid forms include solutions, suspensions and emulsions.
  • a low melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted, and the active ingredient is dispersed homogeneously therein as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool and thereby solidify.
  • compositions of the present invention may be formulated in sustained release form to provide the rate-controlled release of any one or more of the components or active ingredients to optimize therapeutic effects, i.e., antiviral activity and the like.
  • Suitable dosage forms for sustained release include layered tablets containing layers of varying disintegration rates or controlled release polymeric matrices impregnated with the active components and shaped in tablet form or capsules containing such impregnated or encapsulated porous polymeric matrices.
  • the one or more Amido-Substituted Heterocyclic Compounds are administered orally.
  • the one or more Amido-Substituted Heterocyclic Compounds are administered intravenously.
  • the one or more Amido-Substituted Heterocyclic Compounds are administered sublingually.
  • a pharmaceutical preparation comprising at least one Amido- Substituted Heterocyclic Compound is in unit dosage form.
  • the preparation is subdivided into unit doses containing effective amounts of the active components.
  • compositions can be prepared according to conventional mixing, granulating or coating methods, respectively, and the present compositions can contain, in one embodiment, from about 0.1% to about 99% of the Amido-Substituted Heterocyclic Compound(s) by weight or volume.
  • the present compositions can contain, in one embodiment, from about 1% to about 70% or from about 5% to about 60% of the Amido-Substituted Heterocyclic Compound(s) by weight or volume.
  • a total daily dosage of the at least one Amido-Substituted Heterocyclic Compound(s) alone, or when administered as combination therapy can range from about 1 to about 2500 mg per day, although variations will necessarily occur depending on the target of therapy, the patient and the route of administration. In one embodiment, the dosage is from about 10 to about 1000 mg/day, administered in a single dose or in 2-4 divided doses.
  • the dosage is from about 1 to about 500 mg/day, administered in a single dose or in 2-4 divided doses. In still another embodiment, the dosage is from about 1 to about 100 mg/day, administered in a single dose or in 2-4 divided doses. In yet another embodiment, the dosage is from about 1 to about 50 mg/day, administered in a single dose or in 2-4 divided doses. In another embodiment, the dosage is from about 500 to about 1500 mg/day, administered in a single dose or in 2-4 divided doses. In still another embodiment, the dosage is from about 500 to about 1000 mg/day, administered in a single dose or in 2-4 divided doses. In yet another embodiment, the dosage is from about 100 to about 500 mg/day, administered in a single dose or in 2-4 divided doses.
  • compositions of the invention can further comprise one or more additional therapeutic agents, selected from those listed above herein.
  • the present invention provides compositions comprising: (i) at least one Amido-Substituted Heterocyclic Compound or a pharmaceutically acceptable salt thereof; (ii) one or more additional therapeutic agents that are not an Amido-Substituted Heterocyclic Compound; and (iii) a pharmaceutically acceptable carrier, wherein the amounts in the composition are together effective to treat herpesvirus infection.
  • the present invention provides compositions comprising a Compound of Formula (I) and a pharmaceutically acceptable carrier.
  • compositions comprising a Compound of Formula (I), a pharmaceutically acceptable carrier, and a second therapeutic agent selected from the group consisting of anti-herpes agents and immunomodulators.
  • compositions comprising a Compound of Formula (I), a pharmaceutically acceptable carrier, and two additional therapeutic agents, each of which are independently selected from the group consisting of anti-herpes agents and immunomodulators.
  • the present invention provides a kit comprising a therapeutically effective amount of at least one Amido-Substituted Heterocyclic Compound, or a pharmaceutically acceptable salt, solvate, ester or prodrug of said compound and a pharmaceutically acceptable carrier, vehicle or diluent.
  • the present invention provides a kit comprising an amount of at least one Amido-Substituted Heterocyclic Compound, or a pharmaceutically acceptable salt, solvate, ester or prodrug of said compound and an amount of at least one additional therapeutic agent listed above, wherein the amounts of the two or more active ingredients result in a desired therapeutic effect.
  • the one or more Amido-Substituted Heterocyclic Compounds and the one or more additional therapeutic agents are provided in the same container.
  • the one or more Amido-Substituted Heterocyclic Compounds and the one or more additional therapeutic agents are provided in separate containers.

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Abstract

La présente invention concerne de nouveaux composés hétérocycliques à substitution amido de formule (I) : (I) et leurs sels pharmaceutiquement acceptables, X, R1, R2, R3 et R4 étant tels que définis dans la description. Cette invention concerne également des compositions comprenant au moins un composé hétérocyclique à substitution amido, et des procédés d'utilisation desdits composés hétérocycliques à substitution amido pour traiter ou prévenir l'infection à herpèsvirus chez un patient.
EP20902205.2A 2019-12-20 2020-12-16 Composés hétérocycliques à substitution amido et procédés d'utilisation desdits composés pour traiter les herpèsvirus Pending EP4076457A4 (fr)

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